This invention relates to methods and compositions for treating painful conditions of the anal region and more particularly for treating anal fissures, thrombosed or inflamed hemorrhoids, pain associated with the after effects of anal surgery (such as rubber-band ligation of internal hemorrhoids) and chronic anal pain.
Pain in the anal region is often associated with spasm of the anal sphincter. Sphincters are circular groups of smooth muscle that control the orifices of hollow organs. Sphincters are present throughout the gastrointestinal (GI) tract and function to control the passage of materials through this system of the body. When constricted, the sphincters close orifices leading to the hollow organs, such as the stomach, intestine, anus, etc. In order for the sphincter to open, the muscles must relax.
The sphincter that closes the anus (sphincter ani) consists of two sphincter muscle groups. The external anal sphincter is a thin flat plane of striated muscle fibers adherent to the integument surrounding the margin of the anus. The internal anal sphincter (IAS) is a ring of smooth muscle that surrounds the lower extremity of the rectum. Local inflammation can cause sphincter spasm and consequent pain. Dilation of the veins in the anorectal area results in the condition known as hemorrhoids. Frequently, hemorrhoids are accompanied by bleeding, thrombosis, inflammation, and pain in the rectal area. The pain associated with hemorrhoids is due primarily to the combination of inflammation adjacent to the anal sphincters, and spasm of the internal anal sphincter.
Anal fissures are breaks in the integrity of the anal mucosa. Anal fissures can be an extremely painful condition. The primary reason for severe pain is spasm of the internal anal sphincter (IAS). This spasm causes ischemia, which both produces pain and interferes with healing (Sharp, American Journal of Surgery, 1996 171:512-515; Schouten et al., Scandinavian Journal of Gastroenterology, Supplement, 1993 31(218):78-81). Spasm of the anal sphincter, as noted above, also plays a role in the pain of inflammatory conditions of the anal region, such as inflamed or recently thrombosed hemorrhoids (Janicke & Pundt, Emergency Medicine Clinics of North America, 1996 14:757-788). (See also, Madoff, New England Journal of Medicine, January 22, 1998, 338,(40):217-220). Prolonged spasm of the IAS causes ischemia of the muscle, generating a chemical stimulus to nociceptive nerves in the anal region.
Effective treatments for anal fissures, whether medical or surgical, involve both relaxation of the spastic muscle and relieving pressure in the anal canal, which is largely determined by the intensity of the contraction of the IAS. These treatments include lateral sphincterotomy, injection of the sphincter with botulinum toxin (Maria et al., Ann Surg, 1998 November, 228(5):664-9), and application of nitroglycerin ointment (Manookian et al.; Ann Surg 1998 October, 64(10):962-4; Lund and Scholefield Br J Surg 1996 October, 83(10):1335-44; Schouten et al.; Scand J Gastroenterol Suppl 1996 218:78-81). A recent review by Sharp (Sharp, Am J Surg 1996 May,171(5):512-5) of treatment for chronic anal fissures recommends beginning with nitroglycerin ointment. If the fissure has not healed in six weeks, botulinum toxin injections are given. That review notes that "considerable educational effort is required to successfully adjust the dose" of nitroglycerin (Sharp, 1996, supra.). It states that nitroglycerin "will often eliminate the severe pain of fissure-in-ano in 1 day". Schouten et al. (1993, supra.) used topical isosorbide dinitrate to treat chronic anal fissures, attaining pain relief" within 10 days". Lund & Scholefield (Lancet, 1997 349:11-14) reported a randomized controlled trial of 0.2% nitroglycerin ointment for anal fissure. At 2 weeks, pain on defecation, as measured by a visual analogue scale (0=no pain, 100=worst pain ever), averaged 33.5 in the treated group, compared with 48.0 in a group treated with placebo, and 73.0 in the same patients at baseline.
Nitroglycerin has been reported to diminish the pain of thrombosed external hemorrhoids (Gorfine, Dis Colon Rectum 1995 May, 38(5):453-6). The final common pathway for the relaxation of the IAS in response to various stimuli is the release of nitric oxide. Nitric oxide is a known modulator of sphincter tone and acts as an antispasmodic by bringing about a concentration-dependent reduction in the resting tension of IAS. This was demonstrated in vitro by Rattan et al. (Am. J. Physiol., 1992 262:G107-112) in a muscle strip preparation. It is thought that nitric oxide or nitric oxide-liked substances serve as important control mechanisms for the general phenomenon of gastrointestinal adaptive relaxation. In U.S. Pat. No. 5,504,117, Gorfine establishes the use of nitric oxide donors in general, alone or in combination with local anesthetics, for the treatment of anal fissures. Subsequently, in U.S. Pat. No. 5,693,676, Gorfine further establishes the use of nitric oxide donors for treatment of anal disorders.
Despite positive clinical trials, nitroglycerin has not been universally accepted as a treatment for anal fissure. According to an experienced rectal surgeon and a gastroenterologist with a special interest in the colon and rectum (Wrobleski, 1997, personal communication), many patients simply do not get adequate pain relief from nitroglycerin, even in concentrations as high as 0.5%. My experience with one patient was that nitroglycerin relieved the pain, but only at a concentration that caused a significant headache. Moreover, the patient's anal pain recurred within two hours. The reviews cited above point out additional problems, including the full day sometimes needed before pain is relieved, and compliance problems because of headaches and the need for frequent dosage adjustments (Sharp, 1996, supra.). The problems of inadequate relief, short duration of relief, and intolerance of the drug were also described in a recent prospective study of 19 outpatients with chronic anal fissure (Watson et al., British Journal of Surgery, 1996 83:771-775). In this study, of the 15 patients who used nitroglycerin for 6 weeks and returned for a second visit, only 6 were symptom-free.
Several additional approaches are known for relaxation of the IAS. In U.S. Pat. No. 5,595,753, Hechtman sets forth the use of L-arginine as an active ingredient in topical formulations and methods for treating hemorrhoidal pain and sphincter spasm in the gastrointestinal tract. L-arginine acts to increase nitric oxide production. Application of L-arginine in a topical carrier directly to the affected area relaxes sphincter tension and relieves hemorrhoidal pain in approximately 10 minutes. A separate approach, described by Parischa and Kallo in U.S. Pat. No. 5,437,291, makes use of direct injections of botulinum toxin into the affected area for treatment of gastrointestinal muscle disorders and other smooth muscle dysfunction. They report that the benefits of botulinum toxin injection appear to be sustained for several months.
A second source of pain in anal fissures and related conditions is inflammation and irritation of inflamed areas by the fecal stream. In U.S. Pat. No. 4,945084 and U.S. Pat. No. 5,478,814, both by Packman, the use of sucralfate and other related polysaccarides is taught for the treatment of anal conditions, where sucralfate forms an antiinflammatory, antibacterial, and protective coating of the skin lesion. Sucralfate is a polysaccharide originally marketed as a treatment for peptic ulcer disease. Sucralfate has since been used with success for a variety of ulcerative conditions of the skin and of mucosa, including skin ulcers and excoriations (Hayashi et al., J Pediatr Surg, 1991 November, 26(11): 1279-81), solitary rectal ulcers (Spiliadis et al., Gastrointestinal Endoscopy, 1989 35:131-132), and ulcerative colitis (Riley et al., Scandinavian Journal of Gastroenterology, 1989 24:1014-1018). Sucralfate, when applied to a damaged mucosa, forms an adherent film that protects the mucosa and promotes healing (Kochhar et al., Diseases of the Colon and Rectum, 1990 33:49-51). In addition, sucralfate lowers local levels of the inflammatory mediator PGE.sub.2 (Zahavi et al., Diseases of Colon and Rectum, 1989 32:95-98).
Lidocaine, a topical anesthetic, has been used as a treatment for another painful rectal condition, ulcerative proctitis (Bjorck et al., Scandinavian Journal of Gastroenterology, 1989 24:1061-1072). It has also been recommended to relieve pain sufficiently to permit rectal examination of patients with fissures. However, it is not uncommon for pain relief to be insufficient, so that the physician must resort to anesthesia or intravenous sedation, or wait for improvement with conservative treatment (Janicke & Pundt, 1996, supra.)
Sucralfate, a polysaccharide originally marketed as a treatment for peptic ulcer disease, has since been used with success for a variety of ulcerative conditions of the skin and of mucosa, including pressure ulcers (bedsores), solitary rectal ulcers (Spiliadis et al., Gastrointestinal Endoscopy, 1989, 35:131-132), and ulcerative colitis (Riley et al., Scandinavian Journal of Gastroenterology, 1989, 24:1014-1018). It has not been reported as a treatment for anal fissures. Sucralfate, when applied to a damaged mucosa, forms an adherent film that protects the mucosa and promotes healing (Kochhar et al., Diseases of the Colon and Rectum, 1990 33: 49-51). In addition, sucralfate lowers local levels of the inflammatory mediator PGE.sub.2 (Zahavi et al., Diseases of Colon and Rectum, 1989 32:95-98).
In co-pending, commonly-owned U.S. patent application Ser. No. 09/031,858, incorporated by reference herein, I show that sucralfate, together with nitroglycerin, lidocaine, or both, is efficacious for the treatment of anal fissures, and inferred its utility for other painful conditions of the anal region. I suggested that the three ingredients would show synergy in the treatment of these disorders, and presented several cases in which they were particularly effective in relieving pain and promoting healing. Experiments with patients with anal fissures further demonstrated that all three ingredients together produced a better analgesic effect than any two ingredients together. Topical nitroglycerin has become a standard treatment option for anal fissures by rectal surgeons. However, use of nitroglycerin is limited by the frequent occurrence of headache, which often requires discontinuation of the drug. Moreover, it is not always effective in relieving the pain of anal fissures.
A recent study demonstrates the limitations of nitroglycerin alone in the treatment of anal fissure. Nitroglycerin ointment, approximately 200 mg at a time, was applied topically in different concentrations to the anal margin in patients with chronic anal fissure, both observing fissure healing and monitoring the effect of nitroglycerin on the maximum resting pressure (P) of the internal anal sphincter. (Watson et al., Br. J. Surg. 83:771-5, June, 1996). Nineteen patients with chronic anal fissure were treated with ointment containing increasing concentrations of nitroglycerin (0.2-0.8%), until MRP was reduced by more than 25%. The investigators prescribed for each patient nitroglycerin ointment with the minimum concentration of nitroglycerin that reduced that patient's MRP by at least 25%. The patient applied the ointment to the anal area twice daily for 6 weeks. At 6 weeks, the fissures had healed in 9 patients. Six required sphincterotomy and four were lost to follow-up. Eight of the nine patients with healed fistula required a nitroglycerin concentration well above the minimum concentration of nitroglycerin capable of reducing the resting pressure (0.3% v. 0.2%). Sixteen patients were resistant to the usually effective dose of 0.2% nitroglycerin. Three patients experienced tachyphylaxis, and the duration of action of nitroglycerin was less than the 12 hours reported in control patients. Two patients did not complete the study because of headache.
There exists the need to find an ingredient not previously used the topical treatment of painful conditions of the anal region, that can reduce IAS pressure at non-toxic dosages. Such an ingredient could increase the efficacy of combination preparations for topical treatment of painful anal conditions. The present application describes new pharmaceutical compositions for the treatment of painful conditions of the anal region.